Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes.
The MAP kinase (MAPK) JNK but not ERK is synergistically activated during costimulation of T cells. We examined how protein tyrosine kinases (PTKs) and GTPases differentially regulate JNK and ERK in T cells. While PTKs are not selective, small GTPases display distinct MAPK-activating functions. Whereas Ras activates ERK, Rac activates JNK. Rac cooperates with a Syk-generated signal to enhance JNK activation and appears to be at a nodal point for pathways emanating from CD28, calcineurin, and protein kinase C. AP-1- and NF-AT-dependent reporters are stimulated by Rac and Syk and are dependent on JNK. Unlike Syk, the PTK Lck activates JNK but does not cooperate with Rac, resulting in weak AP-1 and NF-AT activation. Therefore, signals generated by PTKs are functionally distinct and need to be integrated to induce transcriptional responses.
Jacinto
E
E
Department of Pharmacology, University of California, San Diego, La Jolla 92093-0636, USA.
Werlen
G
G
Karin
M
M
D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology; D004357:Drug Synergism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D016758:Genes, jun; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells / Q000201:enzymology; D008213:Lymphocyte Activation / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins / Q000502:physiology; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000201:enzymology* / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D020744:rac GTP-Binding Proteins
D018106:CD28 Antigens; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins